Microglial Calhm2 regulates neuroinflammation and contributes to Alzheimer's disease pathology.

Abstract

Alzheimer's disease (AD) is the most common neurodegenerative disease in the world. Neuronal calcium dysfunction and microglial-mediated neuroinflammation are closely associated with the development of AD. However, it remains unknown whether calcium dysfunction contributes to microglial activation and, in turn, AD pathology in vivo. In this study, we demonstrated that the expression of calcium homeostasis modulator family protein 2 (Calhm2) is increased in an AD mouse model. In <i>5×FAD</i> mice carrying five familial AD gene mutations, both conventional knockout of <i>Calhm2</i> and conditional microglial knockout of <i>Calhm2</i> significantly reduced amyloid β deposition, neuroinflammation, and cognitive impairments. Mechanistically, knockout of <i>Calhm2</i> inhibited microglial proinflammatory activity but increased phagocytic activity, leading to restoration of the balance between inflammation and phagocytosis. In addition, knockout of <i>Calhm2</i> reduced acute LPS-induced neuroinflammation. These results highlight an important role for Calhm2 in microglial activation and provide a potential therapeutic target for diseases related to microglia-mediated neuroinflammation.